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Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes.

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Verbavatz,  Jean-Marc
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Citation

Laulier, C., Barascu, A., Guirouilh-Barbat, J., Pennarun, G., Chalony, C. L., Chevalier, F., et al. (2011). Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes. Cancer Research, 71(10), 3590-3602.


Cite as: https://hdl.handle.net/21.11116/0000-0001-09D3-7
Abstract
Genetic stability requires coordination of a network of pathways including DNA repair/recombination and apoptosis. In addition to its canonical anti-apoptotic role, Bcl-2 negatively impacts genome stability. In this study, we identified the breast cancer tumor suppressor BRCA1, which plays an essential role in homologous recombination (HR), as a target for Bcl-2 in the repression of HR. Indeed, ionizing radiation-induced BRCA1 foci assembly was repressed when Bcl-2 was expressed ectopically, in human SV40 fibroblasts, or spontaneously, in lymphoma t(14:18) cells and in HeLa and H460 cancer cell lines. Moreover, we showed that the transmembrane (TM) domain of Bcl-2 was required for both inhibition of BRCA1 foci assembly and the inhibition of HR induced by a double-strand break targeted into an intrachromosomal HR substrate by the meganuclease I-SceI. Fluorescence confocal microscopy, proximity ligation assay, and electron microscopy analyses as well as Western blot analysis of subcellular fractions showed that Bcl-2 and BRCA1 colocalized to mitochondria and endoplasmic reticulum in a process requiring the TM domain of Bcl-2. Targeting BRCA1 to the endomembranes depletes BRCA1 from the nucleus and, thus, accounts for the inhibition of HR. Furthermore, our findings support an apoptosis-stimulatory role for the cytosolic form of BRCA1, suggesting a new tumor suppressor function of BRCA1. Together, our results reveal a new mode of BRCA1 regulation and for HR in the maintenance of genome stability. Cancer Res; 71(10); 3590-602. ©2011 AACR.